Synthesis of d1-(methyl)-16,16-(dimethyl-11-alpha, 15-alpha, beta-dihydroxy-9-oxo-2,13,-trans,trans-prostadienoates

ABSTRACT

A conjugate addition reaction and novel intermediate compounds are disclosed, whereby the reaction of ##STR1## with a lithio-cuprate reagent ##STR2## produces compounds of the class: ##STR3## A new process is disclosed for preparing 1-(methyl)-16,16-(dimethyl)-11-alpha-15-alpha-dihydroxy-9-oxo-2,13,trans,trans-prostadienoate, and congeners thereof, including racemic mixtures.

This is a division of application Ser. No. 266,004, filed May 21, 1981,now U.S. Pat. No. 4,360,688.

FIELD OF THE INVENTION

This invention relates to novel compounds useful as precursors in thesynthesis of 1-(methyl)-16,16-(dimethyl)-11-alpha,15-alpha-dihydroxy-9-oxo-2,13,trans,trans-prostadienoate, congenersthereof, and racemic mixtures thereof. The compound named above has beendescribed in the art to be useful for the induction of menses, for theinduction of labor at term, and as an abortifacient; see the papers byK. Matsumoto, et al., which are referred to at p. 77 of the Abstracts ofthe Fourth International Prostaglandin Conference, May 27-31, 1979, andProstaglandins, 15, 907-921 (1978). The compound has the structure##STR4##

The invention also relates to novel processes of synthesizing newcompounds, and from them, synthesizing the abovedescribedprostadienoates, especially the compound of formula (11).

BRIEF SUMMARY OF THE INVENTION

The novel precursor compounds of this invention include the class of2-aryl-thio alkane di-esters and mixed acid-esters represented by theformula ##STR5## wherein the subscript n is an integer from 3-5inclusive, R₁ is a monovalent radical selected from the class consistingessentially of hydrogen and R₂, wherein R₂ and R₃ are selected from theclass consisting essentially of C₁ -C₆ alkyl, and R₂ may be the same asor different from R₃, and wherein Aryl is selected from the classconsisting essentially of phenyl and phenyl substituted with halogen, C₁-C₄ alkyl, C₁ -C₄ alkoxy, and trifluoromethyl.

The various subscripts and symbols for chemical moieties, once definedherein, continue to have the same definition.

The novel precursor compounds also include the class of derivatives offuran represented by the formula ##STR6## wherein R₄ is selected fromthe class of hydrogen, and C₁ -C₆ alkyl, and wherein --W-- is selectedfrom the class consisting of a divalent carbonyl radical ##STR7## and adivalent carbinol radical (--CHOH--).

From the compounds of the preceding paragraph, one may obtain, byprocesses described herein, additional novel compounds which arecyclopentenones of the class represented by the formulas ##STR8##wherein R₅ is a monovalent radical selected from the class consistingessentially of hydrogen and C₁ -C₆ alkyl, wherein --Y-- is selected fromthe class consisting of a divalent unsaturated moiety (trans--CH═CH--)and a divalent aryl thio radical ##STR9## and --Z-- is ##STR10## P₁ is amonovalent radical selected from the class consisting essentially ofhydrogen or P₂. P₂ is a blocking or protective group which is stableunder the conditions of the 1,4 conjugate addition process to whichcompound (14A, when Y is (trans--CH═CH--), is to be subjected, asdescribed hereinafter, and which can thereafter be removed, usually by amild acid treatment, without disruption of the prostaglandin product ofwhich it forms a part. Such protective groups are well-known in the artand may be, for instance, tetrahydropyranyl, trialkylsilyl, such astrimethylsilyl or dimethyl-t-butylsilyl, or alpha-alkoxy ethyl.

When in compounds of formula (14A), P₁ and R₅ are each hydrogen, and Yis trans--CH═CH--, the compound is the racemic mixture of the 2-transisomer of the 5-cis isomers of the compounds of formulas 23 and 24depicted in U.S. Pat. No. 4,061,670, at column 12.

Broadly described, the novel processes of this invention includepreparing compounds of formula (12), by reacting a 2-halo-alkanedioatediester with an alkali metal thio monocyclic aryl compound to form the2-arylthio-alkanedioate diester. The ester radical which is lesssterically hindered is then cleaved from the alkanedioate by hydrolysis,advantageously with a strong hydroxide, to form a mixed acid-ester. Thelatter is then reacted with an anhydride or an acyl halide to form amixed anhydride, which in turn is reacted with furan to produce an acylfuran of the class of formula (13) when W is carbonyl. The carbonylgroup is then reduced by reaction with a carbonyl reducing reagent,preferably a borohydride, to form a furyl carbinol of formula (13) whenW is --CHOH--. The carbinol moiety is then subjected to an acidcatalyzed re-arrangement and isomerization, and optionallyesterification, to form, via the intermediate 3-hydroxy isomer (14B),the 4-hydroxy cyclopentenone compounds of formula (14A) wherein Y is adivalent aryl thio radical. The aryl thio radical is oxidized to an arylsulfoxy radical and the 2-trans olefinic compound of formula (14A) (whenY is trans--CH═CH--) is formed by thermolysis with a peroxy organicacid.

The 4-hydroxy group of the cyclopentenone is then protected (forsubsequent reactions) with an appropriate blocking group P₂.

It has been unexpectedly discovered that the beta-branch ofprostaglandin-type compounds can then be added at the 3-cyclopentenonylposition of compounds of formula (14A) (in which Y is (trans--CH═CH--))by reaction with a lithio-cuprate reagent, or a functional equivalentthereof, which is capable of furnishing a prostaglandin beta-chainhaving the formula ##STR11## wherein P₃ is a monovalent protectivegroup, to produce compounds having the formula ##STR12## wherein m is aninteger from 2-4 inclusive. Such lithio-cuprate reagents, or theirfunctional equivalent, are disclosed in J. Org. Chem., 43, 3450 (1978).Protective group P₃ should have the same characteristics described abovein respect of P₂, and may be the same chemical moiety as, or may bedifferent from, P₂.

The blocking groups P₂ and P₃ are then removed by hydrolysis to producea racemic mixture. Where, in formula (16), n is 4, m is 3, and R₅ ismethyl, the product of the foregoing comprises a mixture of11-alpha-hydroxy, 15-alpha,beta-hydroxy isomers of the compound offormula (11). This mixture can be resolved by chromatography into theindividual isomers, and dl-(methyl)-16,16-(dimethyl) 11-alpha,15-alpha-(dihydroxy)-9-oxo-2,13-trans,trans-prostadienoate isolatedtherefrom.

The dotted lines shown in the formulas depicted herein indicate that thesubstituents are in the alpha configuration, i.e., below the plane ofthe cyclopentenonyl ring.

Many of the compounds described herein possess asymmetric centers andthus can be produced as racemic mixtures or as individual enantiomers.The racemic mixtures can be resolved if desired at appropriate stages bymethods known to those skilled in the art, to obtain the respectiveindividual enantiomers. It is to be understood that the racemic mixturesand the individual enantiomers are encompassed within the scope of thesubject matter claimed herein.

DETAILED DESCRIPTION

The novel compounds disclosed herein may be prepared from a2-halo-alkane diester having the formula ##STR13## wherein the halo atommay be chlorine, bromine, or iodine. The 2-bromo-di-ethyl ester istaught in Ber., 89, 51, (1956).

The overall process will be explained in conjunction with Flowchart A.##STR14##

In accordance with Flowchart A, a 2-halo-diester of formula (101) isreacted, in Step A, with an alkali metal thioaryloxide to produce a2-arylthio-alkanedioate of formula (103). The alkali metal (AM₁) may beany of sodium, potassium or lithium. The aryl moiety of thethioaryloxide is the same as the Aryl moiety defined above. The reactionis preferably conducted in an alcoholic solution.

The 2-arylthio compound of formula (103) is hydrolyzed in Step B toproduce the monoester of formula (104), the less-sterically hinderedester moiety being cleaved. A strong hydroxide is preferred for thehydrolysis.

The monoester of formula (104) is reacted in Step C with an anhydride offormula (105A) or an acyl halide of formula (105B) to produce the mixedanhydride of formula (106). In the reactants of formulas (105A) and(105B), R₆ and R₇ are selected from the class consisting of C₁ -C₃ alkyland halo-substituted C₁ -C₃ alkyl, and R₆ is preferably the same as butmay be different from R₇. Advantageously a reactive anhydride such as(F₃ C--CO)₂ O is employed.

The mixed anhydride of formula (106) is reacted in Step D with furan toproduce a new class of acyl furan compounds of formula (107).

The compound of formula (107) is hydrolyzed in Step E, to form the acylfuran acid of formula (108).

The reactions of Steps C, D and E may optionally and advantageously beconducted in a single reaction zone without intermediate separation ofthe compounds of formulas (106) and/or (107).

The carbonyl moiety of formula (108) is reduced in Step F to a carbinolmoiety to produce a new class of furyl carbinol compounds of formula(109), employing for the purpose a carbinol reducing reagent, such as aborohydride, e.g., sodium borohydride, in a solvent such as glyme.Preferably the reduction reaction of Step F is conducted in the presenceof a salt of a weak acid, such as sodium carbonate or sodium acetate, toaid in the dissolution of the acyl furan of formula (108).

The furyl carbinol compound of formula (109) is then, in Step G,subjected to an acid catalyzed rearrangement to produce a racemicmixture of the isomers of formulas (110A) and (110B). The rearrangementis accomplished with an aqueous solution of a weak organic acid such asformic acid, or alternatively with an aqueous acidic phosphate buffersolution having a pH of about 3 (Step G-1). The resulting solution of3-hydroxy (110A) and 4-hydroxy (110B) cyclopentenone isomers is thenisomerized (Step G-2), advantageously in the same reaction zone, to thedesired 4-hydroxy isomer of formula (110B) by the addition of a strongacid, such as sulfuric acid.

The compound of formula (110B) is then advantageously esterified byalkylation with, for instance, an alkyl halide (R₅ -X) such asmethyliodide, to form a compound of formula (111). Preferably, the alkylmoiety of such halide is selected to be the desired ester moiety (R₅) ofthe alpha-chain of the ultimately desired prostaglandin-type compound,e.g., a compound of formula (117).

The 2-arylthio moiety of formula (111) is removed and the 2,3-positioncarbons converted to a 2-trans double bond in Step J by reacting thecompound of formula (111) with a peroxy organic acid in a suitablesolvent to form an intermediate sulfoxide compound, which is thensubjected to thermolysis (e.g., heated for an extended period at refluxtemperature) until completion of the formation of a new class of 2-transolefinic compounds of formula (112). The peroxy acid may be aliphatic oraromatic, and may be substituted, for example, peroxy acetic acid,peroxybenzoic acid or meta-chloro-peroxybenzoic acid. The solvent may bea halogenated lower alkane such as dichloromethane.

The hydroxyl moiety of the compound of formula (112) is provided in StepK with a protective group P₂ capable of subsequently being easilyremoved without affecting the rest of the molecule, to form a compoundof formula (113). Advantageously, P₂ is trimethylsilyl ortetrahydropyranyl.

A conjugate addition reaction is conducted in Step L by reacting acompound of formula (113) with a lithio-cuprate addition reagent capableof furnishing a prostaglandin beta-chain having the formula (15),advantageously the reagent shown by formula (114), to produce a racemicmixture of compounds of formula (115).

Unexpectedly, the trans--CH═CH-- moiety of the lithio-cuprate reagent(15) or (114) adds to the 3-position of the cyclopentenonyl moiety ofthe compounds of formula (113), rather than to the alpha-side chain offormula (113).

The protecting groups P₂ and P₃ which are stable to conjugate additionconditions are then removed, and the hydroxy moieties re-created, byhydrolysis in Stem M, employing, for instance, acetic acid, to produce adl-racemic mixture of 15-alpha, beta-dihydroxy isomers of compounds offormula (116). Such mixture is then resolved by chromatography toisolate the desired isomers, which, when in formula (116) n is 4, m is3, and R₅ is methyl, include the prostandionate of formula (11).

It should be understood that in the foregoing description of FlowchartA, the compounds of formulas (110A and B), (111), (112) and (113) areracemic mixtures of optically active isomers. At any desired point isthe process sequence, any of such mixtures can be resolved by theapplication of known chromatographic techniques into the respectiveoptically active isomers and the process sequence continued with eitherof the isomers alone. Likewise, the racemic mixture of compounds offormula (115) may be resolved before Step M, rather than after Step M,into the individual 15-alpha and 15-beta isomers. In separationsconducted after Step M, such isomers may be obtained in their nat.configuration.

The compounds of this invention are also useful for the preparation of acompound of formula (118) ##STR15## which is of potential use for thetreatment of angina and as an inhibitor of blood platelet aggregation;see Tsuboi, et al., Arch. int. Pharmacodyn., 247, 89 (1980) and ThrombusResearch, 20, 573 (1980). The compound of formula (118) is prepared inthe same manner as the compounds of formula (117) by substitution, forthe reagent having the formula (114), of a compound having the formula:##STR16##

The invention will be described in greater detail in conjunction withthe following examples.

EXAMPLE 1 Preparation of Diethyl-2-phenylthio-1,8-octanedioate

To a stirred solution of 175 ml. of 1.5M sodium ethoxide in ethanol at0° C. is added to a solution of 29.8 g. of benzenethiol in 30 ml. ofethanol over 10 minutes. After 10 minutes this solution is treated witha solution of 79.5 g of diethyl-2-bromo-1,8-octanedioate (see. Ber., 89,51 (1956)) in 70 ml. of ethanol during 15 minutes. The resulting mixtureis stirred at ambient temperature for 60 minutes, then at reflux for 60minutes, cooled to room temperature, treated with 3.0 ml. of glacialacetic acid and concentrated in vacuo. The residue is partitioned withwater and ether. The ether layer is washed with water and brine, driedand evaporated. The residue is distilled to provide the product as alight yellow oily liquid, b.p. 165°-180° C. (0.15 mm Hg).

EXAMPLE 2 Preparation of Ethyl-7-carboxy-2-phenylthioheptanoate

To a stirred, ice-cold solution of 20.4 g. ofdiethyl-2-phenylthio-1,8-octanedioate in 100 ml. of ethanol is addeddropwise a solution of 2.41 g. of sodium hydroxide in 12 ml. of waterduring 5 minutes. The resulting solution is maintained at 0° C. for 3.5days and then at ambient temperature for 2 hours. The bulk of theethanol is removed in vacuo and the residue is partitioned with etherand water. The aqueous layer is acidified with dilute hydrochloric acidand the acidic materials are extracted with ether. This extract iswashed with water and brine, dried and concentrated. The residue issubjected to dry column chromatography on silica gel with 30:20:1 ethylacetate-heptane-acetic acid providing the product as a light yellow oil.Its infra-red spectrum has peaks at 1735 and 1700 cm⁻¹.

EXAMPLE 3 Preparation of 8-(2-furyl)-8-oxo-2-phenylthiooctanoic acid

To a stirred, ice-cold solution of 7.75 g. ofethyl-7-carboxy-2-phenylthioheptanoate in 25 ml. of dichloromethane isadded 3.5 ml. of trifluoroacetic anhydride during 2 minutes. Thesolution is stirred at ambient temperature for 10 minutes, recooled to0° C. and treated with 9 ml. of furan during 2 minutes. The resultingsolution is stirred at ambient temperature for 18 hours and thenpartitioned with 1:1 ether-petroleum either and aqueous sodiumbicarbonate. The organic phase is washed with water and brine, dried andevaporated. The resulting crude ester (6.75 g.) is dissolved in 75 ml.of ethanol containing 4.95 g. of 85% potassium hydroxide and 10 ml. ofwater. This solution is refluxed for 20 minutes, cooled and concentratedin vacuo. The residue is partitioned with water and ether. The aqueouslayer is acidified with dilute hydrochloric acid and extracted withether. This extract is washed with water and brine, dried andevaporated, giving the product as an oil, identified as having a PMRδ2.80 (2, t, J=7).

EXAMPLE 4 Preparation of 8-(2-Furyl)-8-hydroxy-2-phenylthiooctanoic acid

To a stirred solution of 3.61 g. of8-(2-furyl)-8-oxo-2-phenylthiooctanoic acid, 5.45 ml. of 1M aqueoussodium carbonate, 25 ml. of water and 15 ml. of glyme is added 0.41 g.of sodium borohydride in portions during one minute. The resultingmixture is stirred at ambient temperature for 3.5 hours, diluted withethyl acetate and acidified cautiously at 0°-10° C. with dilutehydrochloric acid. The organic layer is washed with water and brine,dried and evaporated, giving 3.54 g. of the product as an oil identifiedby its PMRδ 4.800 (1, t, J=7).

EXAMPLE 5 Preparation of7-(4-Hydroxycyclopent-2-en-1-on-2-yl)-2-phenylthioheptanoic acid

To a stirred solution of 54.4 g. of8-(2-furyl)-8-hydroxy-2-phenylthiooctanoic acid in 815 ml. of glyme and610 ml. of water is added successively 0.5 g. of hydroquinone, 12.0 g.of sodium bicarbonate and 122 ml. of 90% formic acid. The resultingsolution is heated at reflux temperature for 24 hours, cooled to 50° C.to produce a mixture of the 3-hydroxy and 4-hydroxy isomers. This isthen treated dropwise with 40 ml. of concentrated sulfuric acid during15 minutes. The resulting solution is refluxed for 18 hours, cooled,diluted with ethyl acetate and then saturated with sodium chloride. Theorganic layer is separated, washed with brine, dried and concentrated.The residue is subjected to chromatography on silica gel with chloroformprogressively enriched in ether, giving 13.0 g. of the product as anoil, identified by its PMRδ 4.94 (1, broad s, CHOH).

EXAMPLE 6 Preparation of Methyl 7-(4-hydroxycyclopent-2-en-1-on-2-yl)-2-phenylthioheptanoate

A stirred mixture of 4.38 g. of7-(4-hydroxycyclopent-2-en-1-on-2-yl)-2-phenylthioheptanoic acid, 1.99g. of potassium carbonate, 1.63 ml. of iodomethane and 26 ml. of acetoneis refluxed for 3.5 hours. The acetone is evaporated and the residue ispartitioned between water and ether. The ether layer is washed withbrine, dried and concentrated, giving the product as an oily liquid,identified by PMRδ 3.67 (3, s).

EXAMPLE 7 Preparation of Methyl7-(4-hydroxycyclopent-2-en-1-on-2-yl)hept-2-trans-enoate

To a stirred, ice-cold solution of 5.20 g. of methyl7-(4-hydroxycyclopent-2-en-1-on-2-yl)-2-phenylthio-heptanoate in 50 ml.of dichloromethane is added a solution of 3.33 g. of 85%m-chloroperoxybenzoic acid in 100 ml. of dichloromethane during 45minutes. After 2 minutes the mixture is treated with aqueous sodiumsulfite and diluted with ether. The organic layer is separated, washedwith sodium bicarbonate solution and brine and dried. The 5.5 g. of oilresidue obtained an evaporation is dissolved in 150 ml. of glyme andheated at reflux for 5 hours. Evaporation of the solvent gives a crudeproduct which is subjected to dry column chromatography on silica gelwith 100:1 ethyl acetate-acetic acid, giving the product as a lightyellow oily liquid, identified by PMRδ 5.75 (1,d, J=15, ═CH--CO).

EXAMPLE 8 Preparation of Methyl7-(4-trimethylsiloxycyclopent-2-en-1-on-2-yl)hept-2-trans-enoate

To a stirred mixture of 1.15 g. of methyl7-(4-hydroxycyclopent-2-en-1-on-2-yl)hept-2-trans-enoate in 20 ml. ofpetroleum ether is added 1.2 ml. of bis(trimethylsilylacetamide). Thesolution which forms is allowed to stand at ambient temperature for 1.5hours, then is diluted with petroleum ether, cooled to 0° C. andfiltered. The crude product, obtained on concentration of the filtrate,is short path distilled, giving the product as a light yellow oilyliquid, b.p. 145° C. (0.1 mm Hg).

EXAMPLE 9 Preparation of dl-Methyl 16,16-dimethyl-11-alpha, 15-alpha,beta-dihydroxy-9-oxo-2,13-trans,trans-prostadienoate

To a stirred solution of 1.36 g. of4,4-dimethyl-1-tri-n-butylstannyl-3-trimethylsiloxy-1-trans-octene in2.4 ml. of tetrahydrofuran at -78° C. is added 1.25 ml. of 1.9Mn-butyllithium in hexane. The solution is stirred at -40° C. for 60minutes, cooled to -78° C. and treated with a solution of 0.34 g. ofcopper pentyne in 0.95 ml. of hexamethylphosphorous triamide and 6.0 ml.of ether. The solution is stirred at -78° C. for one hour and treatedwith a solution of 0.62 g. of methyl7-(4-trimethylsiloxycyclopent-2-en-1-on-2-yl)hept-2-trans-enoate in 5.0ml. of ether. The solution is stirred at -40° C. for 1.5 hours, treatedat -78° C. with a solution of 0.3 ml. of glacial acetic acid in 5.0 ml.of ether, diluted with ether and poured into a stirred mixture of 15 ml.of each of saturated ammonium chloride and 1N hydrochloric acid. Theether layer is washed with cold dilute hydrochloric acid, water andbrine, then dried and evaporated, giving 2.14 g. of light yellow liquid.This liquid is treated with 20 ml. of 4:2:1 glacial aceticacid-tetrahydrofuran-water and the resulting mixture is stirred at 40°C. for 45 minutes, then diluted with toluene and evaporated to drynessin vacuo.

The tetrabutylstannane present in the resulting mixture is removed bypassage as a heptane solution through 15 g. of silica gel. The mixtureof prostadienoates is eluted from the silica gel with ethyl acetate.Evaporation of the ethyl acetate gives 1.06 g. of amber oil comprising adi-racemic mixture of the 11-alpha,15-alpha,beta-dihydroxy compounds,the infrared spectrum of which has peaks at 1740, 1665 and 1020 cm⁻¹.

This oil is subjected to dry column chromatography on silica gel usingthe solvent 100:1 ethyl acetate-glacial acetic acid to provide the moremobile 15-beta epimer (147 mg.) and the less mobile 15-alpha-epimer (113mg.) as light yellow oils.

Having thus described the invention, what is claimed is:
 1. A processwhich comprises reacting a cyclopentenone having the formula ##STR17##wherein R₅ is H or C₁ -C₆ alkyl, and Aryl is selected from the groupconsisting of phenyl and phenyl substituted with halogen, C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy and trifluoromethyl; with a peroxy organic acid followedby thermolysis to form a cyclopentenonylalkenyl compound having theformula ##STR18## (ii) protecting the 4-hydroxyl group of thecyclopentenonyl moiety of the preceding compound with a protective groupP₂, said group P₂ being stable to conjugate addition conditions, to forma compound having the formula ##STR19## (iii) reacting the precedingcompound with a lithiocuprate reagent capable of furnishing aprostaglandin beta-chain having the formula ##STR20## wherein P₃ is aprotective group stable to conjugate addition conditions, to form acompound having the formula ##STR21## and (iv) hydrolyzing theprotective groups P₂ and P₃ to obtain a compound having the formula##STR22##
 2. The process of claim 1 wherein R₅ is methyl.
 3. The processof claim 1 wherein P₂ and P₃ are selected from the class consisting oftrimethylsilyl and tetrahydropyranyl, and P₂ and P₃ are the same.
 4. Theprocess of claim 1, which includes the additional step of resolving andseparating at least one optically active isomer.
 5. The process of claim1 wherein said reagent is a lithio-cuprate-1-pentyne.